Abstract
In addition to triggering the activation of B- or T-cell antigen receptors, the binding of a ligand to its receptor at the cell surface can sometimes determine the physiological outcome of interactions between antigen-presenting cells, T and B lymphocytes. The protein SLAM (also known as CDw150), which is present on the surface of B and T cells, forms such a receptor-ligand pair as it is a self-ligand. We now show that a T-cell-specific, SLAM-associated protein (SAP), which contains an SH2 domain and a short tall, acts as an inhibitor by blocking recruitment of the SH2-domain-containing signal-transduction molecule SHP-2 to a docking site in the SLAM cytoplasmic region. The gene encoding SAP maps to the same area of the X chromosome as the locus for X-linked lymphoproliferative disease (XLP) and we found mutations in the SAP gene in three XLP patients. Absence of the inhibitor SAP in XLP patients affects T/B-cell interactions induced by SLAM, leading to an inability to control B-cell proliferation caused by Epstein-Barr virus infections.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Antigens, CD
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B-Lymphocytes / immunology
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Base Sequence
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COS Cells
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Carrier Proteins / genetics*
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Carrier Proteins / physiology
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Cells, Cultured
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Chromosome Mapping
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Cloning, Molecular
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DNA
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Glycoproteins / metabolism*
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Humans
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Immunoglobulins / metabolism*
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Intracellular Signaling Peptides and Proteins*
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Jurkat Cells
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Lymphoproliferative Disorders / genetics*
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Lymphoproliferative Disorders / immunology
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Lymphoproliferative Disorders / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Molecular Sequence Data
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Protein Binding
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-fyn
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Receptors, Cell Surface
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Signal Transduction*
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Signaling Lymphocytic Activation Molecule Associated Protein
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Signaling Lymphocytic Activation Molecule Family Member 1
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism*
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Tissue Distribution
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X Chromosome
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src Homology Domains
Substances
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Antigens, CD
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Carrier Proteins
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Glycoproteins
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Immunoglobulins
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Intracellular Signaling Peptides and Proteins
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Proto-Oncogene Proteins
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Receptors, Cell Surface
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SH2D1A protein, human
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Sh2d1a protein, mouse
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Signaling Lymphocytic Activation Molecule Associated Protein
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Signaling Lymphocytic Activation Molecule Family Member 1
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DNA
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FYN protein, human
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Fyn protein, mouse
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Proto-Oncogene Proteins c-fyn
Associated data
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GENBANK/AF072903
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GENBANK/AF072930
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GENBANK/AF073019